The present invention relates generally to proteins associated with cell proliferative disorders of the colon including primary colon cancer and colon cancer metastases to liver. The invention also relates to proteins associated with normal colon tissue.
Improvements in surgical procedures, adjuvant therapies, and screening programs have facilitated an overall decline in the mortality of colon cancer in the last 20 years (1). Colorectal cancer nevertheless remains a significant disease accounting for 11% of all cancers in the United States with an estimated 130,200 new cases and 48,100 deaths expected in the year 2001 (2). When diagnosed at an early localized stage, five-year survival of colon cancer is 90%. Only 37% of incident cases are diagnosed at this stage, the remainder often presenting to a physician when the tumor has become metastatic.
More effective screening and prevention measures for colorectal cancer are needed to address this public health problem. Early detection procedures for colorectal cancer have included tests for fecal blood or use of endoscopy. The fecal blood test requires significant tumor size (sensitivity of 90% for small polyps and 75% for diminutive polyps) and has a sensitivity of about 26%, which means 74% of patients with malignant lesions will remain undetected (3). The fecal occult blood test fails to detect many early stage colon cancers because little if any blood is released into the stool at that stage. Also the fecal occult test is not very specific as a general screen, subjecting many to needless discomfort and risk in subsequent full bowel examination.
Visualization of precancerous and cancerous lesions by endoscopy is effective in early detection but is an invasive method with attendant significant risk of complications (4,5). For example, the cecum is reached in 80%-95% of procedures (22) and incomplete colonoscopies require either a repeat colonoscopy or supplemental barium enema.
The complications and cost of the colonoscopy are considerable and the appropriate frequently at which this procedure should be used for cancer screening tool is unknown. Furthermore, the procedural competence varies considerably among endoscopists. Thus, colonoscopy is presently not useful for screening the general population for colon cancer.
Much effort over the years has been directed to the identification of improved diagnostic markers for colon cancer that enable reliable early cancer detection or provide early prognostic information. Carcinoembryonic antigen (CEA), which is a tumor-associated glycoprotein, was found to be expressed at increased levels in 95% of colorectal, gastric and pancreatic cancers, and in the majority of breast, lung and head and neck carcinomas (6). Diagnostic blood tests for CEA are in use for following the course of therapy in the management of colorectal cancer. In postoperative follow-up, CEA appears to be a useful marker of recurrence (sensitivity, 77%; specificity 98%), mainly for liver metastasis, but it has also been shown that only half of colorectal cancers shed CEA levels sufficient for their detection in monitoring therapy (7,8).
The utility of CEA in detecting recurrences is controversial and has yet to be widely applied (9,10). Elevated CEA levels have been reported in patients with nonmalignant disease and many patients with colon cancer have normal CEA levels in the serum, especially during the early stage of the disease (7,11). In light of the currently available data, serum CEA determination possesses neither the sensitivity or specificity needed as an early screening test for colorectal cancer in the asymptomatic population (12).
Changes in nuclear shape, size and DNA organization including major morphological transformation are unique characteristics of cancer cells has been used to diagnose cancer. Nuclear structure is determined by the scaffolding of the nucleus, the nuclear matrix. The nuclear matrix consists of the peripheral lamins, protein complexes, an internal ribonucleic protein network, and residual nucleoli (23). The nuclear framework consists of approximately 10% of the nuclear proteins, and is virtually devoid of lipids, DNA, and histones (24). Most of the nuclear matrix proteins identified to date are common to all cell types, but several identified NMPs are tissue and cell line specific and NMPs have been shown to undergo change with differentiation (25, 26).
Cell type-specific “fingerprinting” of aberrant nuclear matrix proteins and their appearance in cancer development has led to the analysis of nuclear matrix protein composition of a variety of tumors in an effort to determine whether these proteins can be developed as diagnostic and/or prognostic markers for cancer. By means of high resolution, two-dimensional electrophoresis, specific nuclear matrix protein alterations have been demonstrated to exist in primary cancers of the prostate, bladder, renal and colon (27-30). The detection of nuclear matrix proteins in the serum of patients with various types of cancer has been accomplished (31).